This invention relates to therapeutically effective compositions and methods for treatment of patients with dyslipidemia, hyperlipidemia, hypercholesterolemia and related conditions comprising a combination in one dosage form of a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or statin and a fibrate formulated together to provide simultaneously a therapeutically effective amount of the hydroxymethylglutaryl coenzyme A reductase inhibitor and a therapeutically effective amount of the fibrate taken into the blood of a patient in need of treatment where the amount of the fibrate taken into the blood is not substantially affected by the presence or absence of food or levels of fat in food taken by the patient proximal to the administration of the dosage form. The compositions of this invention are also useful for the prevention of type III hyperlipoproteinemia in patients prone to that condition.
In particular, this invention relates to an oral dosage form of a pharmaceutical composition comprising a combination or a statin, a carbohydrate bulking agent, and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 80% and especially at least 85% of the quantity of fenofibrate active species, particularly the AUC quantity of fenofibrate active species, provided by said amount to said patient when fed a meal containing fat, especially when fed at least 1000 calories 50% of which are from fat.
In humans, cholesterol and triglycerides (TG) are part of lipoprotein complexes in the bloodstream, and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein, (LDL) and very-low-density lipoprotein (VLDL) fractions. Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL, and released into the plasma. High levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (apo-B, a membrane complex for LDL-C) promote human atherosclerosis, and decreased levels of HDL-C and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Cardiovascular morbidity and mortality in humans can vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.
Orally administered statins are hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are used in patients to lower low density lipoprotein (LDL) cholesterol. Complimentary to this are orally administered fibrates which are used in patients to decrease lipoproteins rich in triglycerides, to increase high density lipoprotein (HDL), and to decrease atherogenic-dense LDL. Patients who take statins or fibrates are frequently on diets with low and variable fat content.
Uptake of a fibrate such as fenofibrate by a patient is sensitive to a positive food effect, hereinafter referred to simply as a food effect. A positive food effect (or food effect) exits when the amount of an active drug taken into the blood from a given oral dosage form by a fasting patient is less than the amount of the active drug taken into the blood from the same dosage form by the same patient who has eaten a fat-containing meal proximal to the time of administration of the dosage form. A negative food effect exits when the amount of an active drug taken into the blood from a given oral dosage form by a fasting patient is more than the amount of the active drug taken into the blood from the same dosage form by the same patient who has eaten a fat-containing meal proximal to the time of administration of the dosage form. The compositions of this invention generally exhibit a positive food effect.
Patients with severe primary hypercholesterolemia often present with blood levels of low density lipoprotein (LDL) cholesterol greater than 190 mg/dl (4.9 mmol/L) and triglyceride levels up to 350 mg/dl (3.9 mmol/L). The use of diet and single-drug therapy does not always decrease LDL cholesterol and triglycerides adequately enough to reach targeted values in patients with primary severe hypercholesterolemia with or without a concomitant increase in triglycerides. In these patients a combination of complementary fibrate therapy and statin therapy can be desirable.
HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A) is the microsomal enzyme that catalyzes the rate limiting reaction in cholesterol biosynthesis (Mevalonate). A statin compound is an HMG-CoA reductase inhibitor that inhibits HMG-CoA reductase, and therefore inhibits or interferes with the synthesis of cholesterol. Inhibition of cholesterol synthesis can lead to a reduction in blood cholesterol levels.
A large number of naturally or synthetically obtained or synthetically modified compounds have been found to inhibit HMG-CoA reductase. These compounds form a category of agents useful for practicing the present invention. Traditionally these agents have been used to treat individuals with hypercholesterolemia. Examples include statins, which are commercially available, such as lovastatin and mevinolin disclosed in U.S Pat. No. 4,231,938, pravastatin and pravastatin sodium disclosed in U.S. Pat. No. 4,346,227, fluvastatin and fluvastatin sodium and XU 62-320 disclosed in EP 0 114 027 and U.S. Pat. No. 4,739,073, atorvastatin disclosed in U.S. Pat. No. 5,273,995, itavastatin also known as NK-104 disclosed in EP304063, mevastatin disclosed in U.S. Pat. No. 3,983,140, rosuvastatin, velostatin and synvinolin and simvastatin disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, cerivastatin and numerous others described in U.S. Pat. Nos. 5,622,985, 5,135,935, 5,356,896, 4,920,109, 5,286,895, 5,262,435, 5,260,332, 5,317,031, 5,283,256, 5,256,689, 5,182,298, 5,369,125, 5,302,604, 5,166,171, 5,202,327, 5,276,021, 5,196,440, 5,091,386, 5,091,378, 4,904,646, 5,385,932, 5,250,435, 5,132,312, 5,130,306, 5,116,870, 5,112,857, 5,102,911, 5,098,931, 5,081,136, 5,025,000, 5,021,453, 5,017,716, 5,001,144, 5,001,128, 4,997,837, 4,996,234, 4,994,494, 4,992,429, 4,970,231, 4,968,693, 4,963,538, 4,957,940, 4,950,675, 4,946,864, 4,946,860, 4,940,800, 4,940,727, 4,939,143, 4,929,620, 4,923,861, 4,906,657, 4,906,624, RE36,520, and U.S. Pat. No. 4,897,402, the disclosures of which patents are incorporated herein by reference.
Lovastatin, an inactive lactone, is a white, nonhygroscopic crystalline powder isolated from a strain of Aspergillus terreus that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile. Lovastatin is hydrolyzed after oral ingestion to the corresponding (beta)-hydroxyacid. This metabolite is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. When formulated for oral administration as Mevacor, tablets can contain 10 to 40 mg of lovastatin together with pharmaceutically acceptable excipients such as cellulose, lactose, magnesium stearate, starch, and butylated hydroxyanisole as a preservative. When taken separately, lovastatin can treat related hyperlipidemia such as reduce plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-C/HDL-C ratio as well as increase HDL-C, and modestly decrease VLDL-C and plasma triglycerides TG. Mevacor can lower total-C and LDL-C to target levels, and reduce elevated total-C and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb). Single daily doses given in the evening can be more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night. A recommended starting dose of Mevacor is preferably given with a meal. 20 mg once a day can be given with the evening meal. Storage between 5-30xc2x0 C. (41-86xc2x0 F.) is preferred.
Fluvastatin (also known as fluvastatin sodium), a synthetic HMG-CoA reductase inhibitor, is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. When formulated for oral administration as Lescol(copyright), capsules can contain 20 to 40 mg of fluvastatin together with pharmaceutically acceptable excipients such as gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide and other ingredients. Fluvastatin sodium reduces Total-C, LDL-C, and apolipoprotein B, and moderately reduces triglycerides (TG) while producing an increase in HDL-C of variable magnitude. Following oral administration, fluvastatin is absorbed rapidly and completely with peak concentrations reached in less than 1 hour. Administration with food reduces the rate but not the extent of absorption. Fluvastatin sodium is indicated as an adjunct to diet in the treatment of elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels in patients with primary hypercholesterolemia and mixed dyslipidemia (Frederickson Type IIa and IIb). It is also indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL cholesterol to target levels.
Atorvastatin (or Atorvastatin calcium 2:1) is a white to off-white crystalline trihydrate powder that is insoluble in aqueous solutions of pH 4 and below, and is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol. When formulated in Lipitor(copyright) tablets for oral administration, tablets can contain 10 to 80 mg of atorvastatin as well as pharmaceutically acceptable excipients such as calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hydroxypropylmethylcellulose, polyethylene glycol, talc, titanium dioxide): polysorbate 80, NF; and simethicone emulsion. Atorvastatin can reduce total-C, LDL-C, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin can also reduce VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin can reduce total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and can increase HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin can reduce intermediate density lipoprotein cholesterol (IDL-C) in patients Keith dysbetalipoproteinemia. Food decreases the rate and extent of drug absorption as assessed by Cmax and AUC, but LDL-C reduction is similar whether atorvastatin is given with or without food. Atorvastatin can be administered as a single dose at any time of the day, with or without food. Atorvastatin can reduce total-C, LDL-C, VLDL-C, apo B, and TG, and can increase HDL-C in patients with hypercholesterolemia and mixed dyslipidemia.
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Simvastatin is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding (beta)-hydroxyacid form which is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. When formulated as Zocor for oral administration, tablets can contain 5 mg to 80 mg of simvastatin as well as pharmaceutically acceptable excipients cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, lactose, magnesium stearate, starch, talc, titanium dioxide as well as other ingredients including butylated hydroxyanisole which can be added as a preservative. Simvastatin shows no fed-fasted effect when administered immediately before a low-fat meal. Simvastatin can reduce total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio as well as decrease TG and increase HDL-C.
Cerivastatin (or Cerivastatin sodium) is a white to off-white hygroscopic amorphous powder that is soluble in water, methanol, and ethanol, and very slightly soluble in acetone. Cerivastatin sodium is a synthetic, enantiomerically pure competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase that catalyzes the conversion of HMG-CoA to mevalonate in an early and rate-limiting step in the biosynthesis of cholesterol. The inhibition of cholesterol biosynthesis reduces the level of cholesterol in hepatic cells which stimulates the synthesis of LDL receptors and increases the uptake of cellular LDL particles. This can lead to a reduction in plasma cholesterol concentration. When formulated as Baycol(copyright), cerivastatin sodium tablets can contain 0.2 to 0.8 mg of cerivastatin sodium for oral administration and can be taken with or without food. Other tablet ingredients can include pharmaceutically acceptable excipients such as mannitol, magnesium stearate, sodium hydroxide, crospovidone, povidone, iron oxide yellow, methylhydroxypropylcellulose, polyethylene glycol, and titanium dioxide. In patients with hypercholesterolemia, cerivastatin sodium can produce reduced levels of plasma total cholesterol, LDL-C, and apolipoprotein B, VLDL-C and plasma triglycerides and increases plasma HDL-C and apolipoprotein A-1. Cerivastatin systemic exposure (area under the curve, AUC) and Cmax are not sensitive to a food effect, but once daily doses of 0.2 mg can be more efficacious than twice daily doses of 0.1 mg. Cerivastatin sodium can be effective as an adjunct to diet to reduce elevated Total-C, LDL-C, apo B, and TG and to increase HDL-C levels in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Types IIa and IIb) when the response to dietary restriction of saturated fat and cholesterol and other non-pharmacological measures alone is inadequate.
Pravastatin (or pravastatin sodium) is a white to off-white, fine or crystalline powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It is soluble in methanol and water ( greater than 300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether. When formulated as Pravachol for oral administration, tablets can contain 10 to 40 mg of pravastatin. Inactive ingredients can include pharmaceutically acceptable excipients such as croscarmellose sodium, lactose, magnesium oxide, magnesium stearate, microcrystalline cellulose, and povidone. A 10 mg tablet can also contain Red Ferric Oxide, a 20 mg tablet can also contain Yellow Ferric Oxide, and a 40 mg tablet can also contain Green Lake Blend (mixture of DandC Yellow No. 10-Aluminum Lake and FDandC Blue No. 1-Aluminum Lake).
Itavastatin is an inhibitor of HMG-CoA reductase and can be dosed in tablets containing from about 1 mg to about 20 mg, preferably from about 2 mg to about 10 mg.
Rosuvastatin is an inhibitor of HMG-CoA reductase and can be dosed in tablets containing from about 4 or 5 mg to about 10 or 20 mg, with reported doses of up to about 80 mg per day when formulated as Crestor.
Preferred statins in this invention are those useful for oral administration. Most preferred statins in this invention include lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin and cerivastatin.
While blood levels of active drug or active species from an oral dose of a fibrate such as fenofibrate in a patient are susceptible to a food effect (i.e., variable uptake between fed and fasted states) leading to variation in the amount of active drug species received from a given dose of a fibrate, the efficacy of most statins is not substantially compromised by the presence or absence of food. In a combination dosage form of a statin and a fibrate such as fenofibrate, intake or absence of intake of food can lead to unexpectedly high or low levels of the active fibrate in the presence of a given dosage level of a statin. This lack of control of fibrate level in the blood can potentially lead to undesired side effects such as myopathy and rhabdomyolysis that have sometimes been seen previously with statins alone and with fibrates and statins when administered concurrently to a patient, particularly as a result of concurrent administration of gemfibrozil and lovastatin. Administration of separate dosage forms of a statin and of a fibrate can also pose the potential for variable uptake of either drug, for example when a patient overdoses or underdoses one or the other individual dosage form by taking more or fewer doses of either separate drug than the patient""s condition would require for treatment. This can happen when a patient forgets to take one or the other drug dosage form, or when the patient forgets that he or she has taken one or the other drug dosage form and subsequently takes a second or even a third or more dosage form of one or both of the drugs. This can be especially prevalent in an older patient and in a patient with a failing memory.
Thus there is a need for a single therapeutically effective oral dosage form comprising a combination of a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or a statin) and a fibrate that provides adequate delivery of both a therapeutically effective amount the HMG-CoA reductase inhibitor (statin) and a therapeutically effective amount of the fibrate active species without substantial variability in the amounts of either of the drugs received in a patient between a fasted and fed states. It is an object of this invention to provide such a dosage form.
In this regard, this invention provides a novel pharmaceutical composition comprising a combination of a hydroxymethylglutaryl coenzyme A reductase inhibitor and a fibrate, particularly fenofibrate, in the form of microparticles of solid fibrate that are stabilized by phospholipid as a surface active substance and that provide reduced in vivo variability in the therapeutically effective amounts of either of the drugs in a patient between a fed and fasted states when administered orally. The present invention further provides novel pharmaceutical compositions comprising a combination of a statin and a fibrate. particularly fenofibrate, in the form of microparticles of solid fibrate that are stabilized by phospholipid as a surface active substance and that provide reduced in vivo variability in the bioavailability of the drug among fed and fasted patients when administered orally.
In particular, the present invention provides a dosage form such as an orally administered dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 80% of the quantity of fenofibrate active species provided by said amount to said patient when fed a meal containing fat.
It has long been known that the bioavailability of many hydrophobic drugs can be improved if the drugs are administered with food, i.e., the drugs exhibit a food effect. A patient is often instructed to take the drug at meal times. Various explanations of the food effect have been advanced including delayed gastric emptying to allow more drug to dissolve before reaching the small intestine thereby producing longer residence times at specific absorption sites in the small intestine; direct interaction and solubilization of drug by food, especially by hydrophobic food components such as fats and lipids; food-related increases in hepatic blood flow to cause a decrease in first-pass metabolism; and increased gastrointestinal secretions that can improve drug solubility.
Dosage forms or quantities of compositions containing a fibrate such as fenofibrate have been marketed and prescribed for the treatment of hypercholesterolemia, hyperlipidemia, hypertriglyceridaemia and related disorders. There have been a number of improvements in dosage forms of fenofibrate in an effort to increase bioavailability of the drug and hence its efficacy. However, there is still a need for a dosage formulation that can substantially reduce or overcome the differential between the bioavailability of the drug in patients who are fasted versus the bioavailability of the drug in patients who are fed.
Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid 1-methylethyl ester is an example of a poorly water-soluble compound. It is a benzophenone containing a para-chlorophenyl group and a para-isopropyloxycarbonylisopropoxyphenyl group, both of which are substantially hydrophobic groups. Fenofibrate exhibits a melting point reported to be in the range of 79 to 82xc2x0 C. (Physician""s Desk Reference, 1999 Edition, pace 477), which is above that of the symmetrically unsubstituted benzophenone with a reported melting point range of 48 to 51xc2x0 C. but below that of the symmetrically substituted 4,4xe2x80x2-dichlorobenzophenone with a reported range of 144 to 146xc2x0 C. (Aldrich Chemical Co. catalog, 1999).
Fenofibrate acts as a potent lipid modulator agent offering unique and significant clinical advantages over existing products in the fibrate class of drugs. Fenofibrate produces substantial reductions in plasma triglyceride levels in hypertriglyceridemic patients and in plasma cholesterol and LDL-cholesterol in hypercholesterolemic and mixed dyslipidemic patients.
Fenofibrate is practically insoluble in water. It is normally poorly and variably absorbed, and has to be taken with food. Fenofibrate is a prodrug that is absorbed and then hydrolyzed by tissue and plasma esterases to fenofibric acid, its active metabolite. The major metabolite of fenofibrate found in blood or plasma, fenofibric acid, has an elimination half-life of approximately twenty hours. Fenofibric acid is a fenofibrate active species responsible for the pharmacological activity of fenofibrate.
Fenofibrate was first available in a pharmaceutical dosage form (Lipidil(copyright)) consisting of a hard gelatin capsule containing fenofibrate and pharmaceutically acceptable excipients such as lactose, pregelatinized starch and magnesium stearate. After oral administration, during a meal, about 60% of the dose of this conventional form is absorbed and found in the blood as fenofibric acid (Weil et al., The metabolism and disposition of 14C-fenofibrate in human volunteers, Drug. Metabol. Dispos. Biol. Fate. Chem., 18 (1990) 115-120).
Historically, in order to improve the intestinal absorption, another pharmaceutical dosage form was introduced (Lipidil Micro(copyright)). European Patent Application 330,532 and U.S. Pat. No. 4,895,726 disclose a fenofibrate composition in which the fenofibrate powder is co-micronized with a solid wetting agent. Sodium lauryl sulfate is described as the wetting agent of choice. The co-micronized powder so obtained is mixed with capsule filling pharmaceutically acceptable excipients such as lactose, starch, cross-linked polyvinyl pyrrolidone (PVP), and magnesium stearate. A study comparing Lipidil Micro(copyright) formulation to the conventional form (Lipidil(copyright)) had showed statistically significant increase in bioavailability with the former but without elimination of food effect. A formulation of fenofibrate that refers to this patent is currently available in the United States under the name Tricor Micronized(copyright).
European Patent Application 724,877 describes fenofibrate powder co-micronized with a wetting agent in association with a vitamin E component (tocopherol and/or its organic acid ester) for treating or preventing disorders associated with lipoprotein oxidation.
U.S. Pat. No. 4,800,079 describes a medicinal composition in the form of granules with controlled release of fenofibrate. Each granule includes an inert core, a layer based on fenofibrate and a protective layer. Fenofibrate is present in the form of crystalline microparticles of dimensions not greater than 30 xcexcm.
U.S. Pat. No. 4,961,890 describes a process for preparing a controlled release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles (less than 30 xcexcm in diameter) within a multilayer inert matrix.
European Patent Application 757,911 describes a fenofibrate pharmaceutical dosage form in which fenofibrate is in solution in diethylene glycol monoethyl ether (EMDG) which is a non-ionic surfactant.
European Patent Application 904,781 describes a process for making granules of a solid dispersion of a disintegrant in molten fenofibrate by blending a solid dispersing agent into molten fenofibrate, cooling and solidifying the bulk mixture in a tray, and then milling the solid through a screen to produce granules. Disintegrants include polymers such as starch, croscarmellose sodium, sodium starch glycolate, and crospovidone which are pharmaceutically acceptable excipients. Such disintegrants are slow to swell and dissolve in aqueous media. Furthermore, when crosslinked as in the case of crospovidone, a polymeric disintegrant will not be uniformly dissolved in molten drug but rather at best will form micro-domains in molten fenofibrate. In addition, polymeric materials can exhibit phase separation phenomena when distributed in a substance with which there is not complete compatibility. This was shown, in part, by Sheu, M. T. et al., xe2x80x9cCharacterization and dissolution of fenofibrate solid dispersion systemsxe2x80x9d, Int. J. Pharm. (1994), 103(2), 137-46 using differential scanning calorimetry measurements that found fenofibrate to be incompatible with poly(vinyl pyrrolidone). Thus, preparation of a bulk mixture in the melt followed by solidification and grinding can lead to non-uniform distributions and compositions in granules. This can adversely effect the bioavailability of the active component.
U.S. Pat. No. 5,700,471 discloses a process for the micronization of compounds having low solubility in water by exposing such compounds briefly to a temperature above their respective melting points, dispersing them with turbulence in an aqueous or organic phase, and subsequently cooling the phase to form a fine particle dispersion. However, it is specified (column 2, lines 1-9) that certain substances and specifically fenofibrate are not amenable to processing entirely without organic solvents because their aqueous dispersions agglomerate and cannot be metered. Thus, in example 2 of U.S. Pat. No. 5,700,471, fenofibrate is not directly dispersed in water but rather is first dissolved in a four-fold excess of a water-miscible organic solvent (isopropanol) which must be removed in a subsequent step. Organic solvents can pose flammability risks, exposure dangers to process operators, potential environmental problems, and added expense related to their storage, ultimate removal from a formulation, and disposal. Thus it is desirable to overcome the use of organic solvents where possible.
U.S. Pat. No. 4,880,634 describes a method of production of an excipient system containing a pharmacologically active substance for peroral administration of lipid nano-pellets in an aqueous, colloidal suspension. The method consists of forming a melt of a mixture of at least one surfactant, a pharmacologically active substance, and at least one lipid, dispersing the molten mixture within an aqueous solution at a temperature above the melting point of the lipid to form lipid nano-pellets, and cooling the suspension below the melting point of the lipid. Animal and plant phospholipids such as lecithin and their hydrogenated forms may be employed in the process although the use of chloroform is taught in examples citing phospholipon 100H. The pharmacologicaily effective substance can be added to the melted lipid in molten form or dissolved or dispersed in the molten lipid.
U.S. Pat. No. 4,895,726 discloses a gelatin capsule dosage form of fenofibrate containing a co-micronized mixture of particles of fenofibrate and a solid surfactant. The dosage form exhibits improved dissolution rate and bioavailability of fenofibrate over that of micronized fenofibrate alone or that of micronized fenofibrate subsequently mixed with solid surfactant. However, the surfactant must be a solid so it can be micronized, and the micronized surfactant in the form of particles is not uniformly juxtaposed or coated on the surface of the fenofibrate particles.
U.S. Pat. No. 5,545,628 discloses a melted and cooled pharmaceutical composition in a hard gelatin capsule for treating hyperlipidemia and/or hypercholesterolemia. The composition contains fenofibrate, one or more polyglycolyzed glycerides, and optionally other polyalkylene glycol polymers that are added to adjust HLB value, melting point, and stability. The composition provides an increased bioavailability of fenofibrate with respect to previously marketed forms of fenofibrate (i.e., non co-micronized Lypantyl 200(trademark) and co-micronized Lypantyl 200 M(trademark)).
U.S. Pat. Nos. 5,645,856 and 6,096,338 disclose a composition and method of improving the in vivo bioavailability of a hydrophobic drug from a pharmaceutical composition comprising the drug dispersed or dissolved in a digestible oil containing a hydrophilic surfactant which substantially inhibits the in vivo lipolysis of the digestible oil, wherein there is added to the composition a lipophilic surfactant capable of reducing the inhibitory effect of the hydrophilic surfactant.
U.S. Pat. Nos. 5,776,495 and 6,027,747 disclose a solid dispersion with enhanced bioavailability of a surface active agent and at least one therapeutic agent in a hydrophilic carrier having enhanced solubility in an aqueous medium. The dispersion is prepared by dissolving the therapeutic agent in a volatile organic solvent containing a very hydrophilic polymer and without strong heat or vacuum evaporating the solvent to dryness to form a co-precipitate of therapeutic agent and hydrophilic polymer.
U.S. Pat. No. 5,827,536 discloses soluble fenofibrate pharmaceutical dosage formulations exhibiting improved bioavailability after oral administration. However, the formulations contain fenofibrate as a solution in a solubilizing agent consisting of diethylene glycol monoethyl ether.
U.S. Pat. No. 6,042,847 discloses a three-phase pharmaceutical form exhibiting constant and controlled release of an amorphous active ingredient stabilized with polymers for a single daily peroral application. The first phase consists of a core containing an amorphous active ingredient. polyvinylpyrrolidone and a cellulose ether as carriers and as inhibitors of its crystallization, and a surfactant that improves the solubility of the active ingredient and promotes the absorption of the amorphous active ingredient from the gastrointestinal tract. The second phase contains a cellulose ether and a mixture of mono-, di- and triglycerides as sustained release agents. The third phase is a poorly soluble or gastro-resistant polymeric film coating
U.S. Pat. No. 6,068,854 discloses a constant release tablet consisting of a matrix of gelatin in which is dispersed as an emulsion, dispersion or colloid a lipophilic and/or poorly water-soluble pharmaceutical substance with a particle size below 200 micrometers.
U.S. Pat. No. 6,074,670 discloses an immediate-release fenofibrate composition comprising an inert hydrosoluble carrier covered with a layer containing fenofibrate in a micronized form having a size less than 20 micrometers, a hydrophilic polymer and, optionally, a surfactant. In an example cited, a suspension of micronized fenofibrate and sodium lauryl sulfate is suspended in a solution of sodium lauryl sulfate and polyvinylpyrrolidone, sprayed onto 100 to 400 micrometers size lactose particles suspended in a fluidized air bed granulator, and the granulate is placed in capsules or transformed into tablets by mixing with cross-linked PVP, microcrystalline cellulose, colloidal silica, and sodium stearyl fumarate. The composition showed enhanced bioavailability of fenofibrate. However, increased dissolution rates of a formulation of fenofibrate do not translate directly or linearly to increase uptake of the drug, and show that an in vitro experimental result can not necessarily predict the results of an in vivo experiment.
It is generally accepted that water insoluble or poorly water-soluble drugs can be made more bioavailable when presented in the form of small particles. In many cases, it is known that small particles must be stabilized against particle size growth and agglomeration by the addition of one or more surface active agents at some poinit in the preparation of the particles, especially in a size reduction process that employs the input of mechanical energy. Because they are biocompatible and well tolerated in vivo, preferred surface active agents or particle stabilizers are phospholipids, and preferred small particles of fenofibrate are stabilized by phospholipid particle stabilizers.
Microparticles of water insoluble or poorly soluble substances are small particles having diameters of from nanometers to micrometers and refer to solid particles of irregular, non-spherical or spherical shapes. When the insoluble and poorly soluble substances are therapeutically and diagnostically useful substances, formulations containing them as microparticles or small particles provide some specific advantages over unformulated non-micronized drug particles. These advantages include improved oral bioavailability of drugs that are poorly absorbed from the GI tract, development of injectable formulations that are currently available only in oral dosage form, preparation of inhaled drugs that otherwise could not be formulated for nasal or aerosol delivery as well as other advantages.
Current technology for delivering insoluble drugs as described in U.S. Pat. Nos. 5,091,188; 5,091,187 and 4,725,442 focuses on (a) either coating small drug particles with surface active substances that are natural or synthetic phospholipids or (b) dissolving the drug in a suitable lipophilic carrier and forming an emulsion stabilized with surface active substances that are natural or semisynthetic phospholipids.
U.S. Pat. No. 5,145,684 discloses methods for preparation and dispersions of particles consisting of crystalline drug substance having a surface modifier or surface active substance adsorbed to maintain an effective average particle size of less than about 400 nm. However, the method requires a milling step that can result in impurities being added to the formulation from fractured milling media.
U.S. Pat. Nos. 5,470,583 and 5,336,507 disclose methods for preparation of nanoparticles using a charged phospholipid as a cloud point modifier.
U.S. Pat. No. 5,302,401 discloses compositions and methods for forming nanoparticles with a surface modifier and a cryoprotectant adsorbed thereon.
International Patent Application WO 99/39700 describes the preparation of submicron nanoparticles from a pharmacologically active principle and a composite material consisting of at least one lipidic substance and at least one amphiphilic substance using high pressure homogenization to form a microemulsion of the composite material at a temperature higher than the melting temperature of at least one of the materials forming the composite and in the presence of one or more aqueous surfactants as surface active substances and then cooling the microemulsion to form a dispersion of solid particles.
U.S. Pat. No. 5,785,976 discloses a heated aqueous emulsification and cooling process for the preparation of solid lipid particles. In that process a solid lipid or bioactive agent or a mixture of solid lipids or bioactive agents is melted and stabilizers, i.e., surface active substances, are added either to the lipid or bioactive agent and to the aqueous phase or to the aqueous phase only. The aqueous phase is heated to the temperature of the melt before mixing and may contain stabilizers, isotonicity agents, buffering substances, cryoprotectants and/or preservatives. The molten lipid compounds and the bioactive agents can be emulsified in the aqueous phase by high-pressure homogenization. The homogenized dispersion is then allowed to cool until solid particles are formed by recrystallization of the dispersed agents. Drugs or other bioactive substances to be incorporated into the particles may be melted together with the lipids or may be dissolved, solubilized or dispersed in the lipid melt before an emulsification by homogenization step.
U.S. Pat. No. 5,922,355 discloses a method for preparing submicron size microparticles by particle size reduction methods in which a solid material is reduced in size over a period of time while continuously below the melting point of the material or by precipitation while the particles are stabilized with phospholipids as surface active substances in combination with other surface modifiers to control growth of particle size and enhance storage stability. The use of one or more surface modifiers in addition to a phospholipid provides volume weighted mean particle size values that are much smaller than what can be achieved using phospholipid alone without the use of an additional surface active substance (surfactant) with the same energy input while providing compositions resistant to particle size growth on storage. The phospholipid and the surfactant are both present at the time of particle size reduction.
WO 00/30616 discloses a rapidly dispersing solid dry dosage form comprised of a water insoluble compound existing as a nanometer or micrometer particulate solid which is surface stabilized by the presence of at least one phospholipid, the particulate solid being dispersed throughout a bulking matrix. When the dosage form is introduced into an aqueous environment, the bulking matrix is substantially completely dissolved within less than 2 minutes thereby releasing the water insoluble particulate solid in an unaggregated and/or unagglomerated state. The matrix is composed of a water insoluble substance or therapeutically useful water insoluble or poorly water-soluble compound, a phospholipid and optionally also at least one non-ionic, anionic, cationic, or amphiphatic surfactant, together with a matrix or bulking agent and if needed a release agent. The volume weighted mean particle size of the water insoluble particle is 5 micrometers or less.
While these disclosures provide compositions and methods to enhance the bioavailability of fenofibrate from various dosage forms, none address the need to substantially reduce or eliminate the food effect observed with fenofibrate, i.e., the difference between the amount of the drug taken up in a patient who is fasting versus the otherwise enhanced uptake of the drug in the patient who is fed (food effect).
Besides the fibric acid derivatives such as fenofibrate, clofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate, simfibrate, theofibrate, pirifibrate, plafibride, and binifibrate, there are a number of other classes of drugs which, when administered to patients, reduce cholesterol and/or lipids. These include bile acid sequesters such as cholestyramine, and meglutol, melinamide, sitosterol, tiadenol, probucol, and nicotinic acid. In addition to these there is a relatively new class of drugs referred to as statins. The latter class of drugs include atorvastin, cerivastatin, epastatin, fluvastatin, itavastatin, lovastatin, mevastatin, pravastatin, rosuvastatin, and simvastatin.
Combination of a statin with a fibrate has been shown to produce beneficial effect in the treatment of hyperlipidemia and hyperlipoproteinemia. However, the fibrates used previously have a limitation related to the presence of a food effect and require patient restrictions and relatively higher dosage amounts of each drug. Surprisingly, the compositions of this invention comprising a fibrate, more specifically fenofibrate, together with a statin are substantiall devoid of food effect, particularly with respect to the uptake of the fibrate.
Raza, et al. in WO 0045817 disclosed safe non-interacting drug combinations of a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor and a drug that is either an inducer, inhibitor, or substrate of cytochrome P 450. Particular combinations are useful in treating hyperlipidemia in humans who are receiving immunosuppressive chemotherapy. A preferred combination is the agent and a fibrate drug, the use of such a combination in treating hyperlipidemia in mammals, and medicaments containing such a combination for use in such treatments, Lipantil(trademark), a brand of fenofibrate used is known to have food effects Pan et al. in J. Clin. Pharmacol. (2000), 40(3), 316-323 reported that concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin in healthy adult volunteers who received single doses of 201 mg fenofibrate alone, 201 mg fenofibrate+40 mg pravastatin, and 40 mg pravastatin alone. However, the combination of fenofibrate and pravastatin was administered as separate dosage forms, and uptake of fenofibrate is subject to a food effect.
Farnier, M. and Dejager, S. in Am. J. Cardiol. (2000), 85(1), 53-57 reported that the addition of fluvastatin to micronized fenofibrate results in substantial improvement in atherogenic plasma lipids levels in severe primary hypercholesterolemia and is well tolerated. Patients received micronized fenofibrate 200 mg, fluvastatin 20 mg plus micronized fenofibrate 200 mg, or fluvastatin 40 mg plus micronized fenofibrate 200 mg. However, the fenofibrate and the statin were administered in separate dosage forms, and uptake of micronized fenofibrate demonstrates a food effect.
Kayikcioglu et al. in Am. J. Cardiol. (1999), 83(7), 1135-1137 reported that simvastatin 10 mg administered on alternate days with fenofibrate 250 mg is as effective as a daily dose of simvastatin 10 mg and fenofibrate 250 mg in lowering plasma cholesterol, triglycerides, and LDL cholesterol, and increasing HDL cholesterol levels in patients with mixed hyperlipidemia. The fenofibrate and simvastatin were administered in separate dosage forms and uptake of fenofibrate is subject to a food effect.
EP 0 475 148 A1 discloses that tablets containing pravastatin in combination with tablets of a fibric acid derivative were useful for prevention or treatment of type III hyperlipoproteinemia.
EP 0 455 042 A1 discloses a combination of pravastatin and fenofibrate in a single capsule for the treatment of dyslipidemia. However, the combination is prepared by grinding a tablet of pravastatin and a tablet of fenofibrate to a powder for use in a single capsule, and this form of fenofibrate exhibits a food effect.
Ippen et al in WO 0037078 describe a combination of the 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor, cerivastatin with fenofibrate and to its use in the prophylaxis and treatment of disorders and diseases of lipid metabolism. The tablets containing the two actives are prepared by standard wet granulation. Such forms of fenofibrate exhibit a food effect.
Canadian patent 2,048,395 provides a method for preventing or treating type III hyperlipoproteinemia by administering pravastatin alone or in combination with a fibric acid derivative such as fenofibrate. Tablets containing pravastatin and fenofibrate alone or in combined were prepared by standard dry granulation method using fenofibrate that is subject to food effect.
It is an object of this invention to provide an orally administered pharmaceutical composition of a statin and a fibrate that provides a therapeutically effective amount of the statin and the fibrate that substantially increases the bioavailability of the fibrate and substantially reduces the difference between the amount of the active species of the drug taken up in a patient who is fasting versus the amount of the active species of the drug in the patient who is fed (i.e., substantially reducing the food effect).
It is another object of this invention to provide an orally administered pharmaceutical composition of a statin and fenofibrate that provides a therapeutically effective amount of the statin and fenofibrate that substantially increases the bioavailability of the fenofibrate and substantially reduces the difference between the amount of the active species of the drug taken up in a patient who is fasting versus the amount of the active species of the drug in the patient who is fed (i.e., substantially reducing the food effect known to be associated with administration of fenofibrate).
It is well accepted in practice that an improved bioavailability of a drug allows for an appropriate reduction in daily dosage amount.
It is another object of this invention to provide an orally administered pharmaceutical composition of a water-soluble statin and fenofibrate that provides a therapeutically effective amount of the statin and fenofibrate that substantially increases the bioavailability of the fenofibrate and substantially reduces the difference between the amount of the active species of the drug taken up in a patient who is fasting versus the amount of the active species of the drug in the patient who is fed (i.e., substantially reducing the food effect known to be associated with administration of fenofibrate).
It is another object of this invention to provide an orally administered pharmaceutical composition of a water insoluble or poorly water-soluble statin and fenofibrate that provides a therapeutically effective amount of the statin and fenofibrate that substantially increases the bioavailability of the fenofibrate and substantially reduces the difference between the amount of the active species of the drug taken up in a patient who is fasting versus the amount of the active species of the drug in the patient who is fed (i.e., substantially reducing the food effect known to be associated with administration of fenofibrate).
It is another object of this invention to provide a combined pharmaceutical dosage form of fenofibrate and a statin that can be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, or other convenient dosage form such as oral liquid in a capsule as known in the art.
It is another object of this invention to provide a once-a-day pharmaceutically effective single dosage form of fenofibrate and a statin that can be administered to a patient in need of treatment while substantially reducing the food effect known to be associated with administration of fenofibrate.
It is another object of this invention to provide a method of treatment of hypercholesterolemia and related diseases of dyslipidemia and dyslipoproteinemia comprising the administration of dosage forms of the compositions of this invention to a patient in need of treatment.
The present invention provides a dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 80% of the quantity of fenofibrate active species provided by said amount to said patient when fed a meal containing fat.
The present invention also provides a dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is greater than 80% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.
The present invention also provides an oral dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species into the blood of said patient when fasted that is between 85% and 115% of the quantity of fenofibrate active species provided by said amount into the blood of said patient when fed at least 1000 calories 50% of which are from fat.
The present invention also provides an oral dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 85% of the AUC quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.
The present invention also provides a dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the microparticles of fenofibrate are prepared by a process comprising the steps of:
(a) mixing at high shear an admixture of fenofibrate and a phospholipid substance in an aqueous carrier in the absence of an organic solvent within a first temperature range at or above the melting point of fenofibrate to form a heated suspension wherein fenofibrate is molten;
(b) homogenizing said heated suspension in a first pressure range and within said first temperature range to form a heated homogenate containing fenofibrate;
(c) cooling said heated homogenate to a second temperature range below the melting temperature of fenofibrate to form a transiently stable cooled homogenate containing fenofibrate;
(d) applying a particle stabilizing energetic process to said cooled homogenate within a second temperature range below the melting temperature of fenofibrate and in a second pressure range to form a cooled dispersion of small particles containing fenofibrate, and
(e) drying said cooled dispersion to form dried small particles containing fenofibrate.
In another aspect, this invention also provides a method of treatment of dyslipidemia and dislipoproteinemia and related diseases in a patient comprising the administration to said patient of a dosage form of the aforementioned pharmaceutical compositions comprising a combination of a statin and microparticles of fenofibrate.
In another aspect, this invention provides a pharmaceutically effective composition comprising small particles of fenofibrate stabilized by a phospholipid stabilizing agent which when dried in the presence of a sugar and optionally also in the presence of a carbohydrate-derived alcohol can be formulated as a capsule or tablet dosage form for oral administration to patients in need of treatment by fenofibrate. The dosage form provides dosage levels of active agent (e.g., fenofibrate active species) into the blood of a fasting patient and into the blood of a fed patient where the amount of drug or active ingredient that the patient receives in the fasted state differs by less than 25%, preferably by less than 20%, more preferably by less than 15%, even more preferably by less than 10%, and most preferably by less than 5% from the amount of drug or active ingredient that the patient receives in the fed state.
In a clinical study using capsule dosage forms and monitoring the pharmacokinetic comparison of a single dose of a phospholipid-stabilized fenofibrate formulation of this invention versus a comicronized fenofibrate (Lipanthyl 67M) dose in healthy volunteers under fed and fasted conditions, distinct advantages are seen. For example, under fasted conditions, the formulation of this invention provides a statistically significant increase in relative bioavailability of fenofibrate over that of a comicronized formulation as evidenced by a higher mean maximum concentration (Cmax) of the drug and a higher mean AUC (area under the curve). This difference between the two formulations substantially disappears under fed conditions.
When the bioavailability of a comicronized (Lipanthyl 67M) formulation under fed conditions is compared to that under fasted conditions, the Cmax significantly increases and the mean AUC""s significantly increases in fed state. In addition, the mean terminal half-life appears to be shortened.
In contrast and unexpectedly when the bioavailability of fenofibrate formulations of this invention are compared under fed versus fasted conditions, the relative increase in Cmax is substantially less than the relative increase seen in the Lipanthyl 67M case in fed state, and the relative increase in mean AUC is substantially less than the relative increase seen in the Lipanthyl 67M case in fed state. The relative bioavailability is approximately substantially close to unity, (within 20%) when comparing fasted versus fed conditions using the formulation of this invention. No significant variation in mean terminal half-life is observed.
The phospholipid-stabilized fenofibrate particle formulation of this invention provides a pharmacokinetic profile in which the effect of ingestion of food on the uptake of the fenofibrate active species is substantially reduced over that observed with the commercially available comicronized formulation.
Statins are subject to substantial first pass metabolism in the liver where they inhibit HMG-CoA reductase to reduce production of cholesterol. Efficacies of statins are not substantially reduced by the presence or absence of food.
Small particles or microparticles of fenofibrate of this invention can be conveniently prepared by a microfluidization process in the form of an aqueous suspension. The microfluidization process is a one- or two-stage size reduction process that can be done in the presence of a liquefied or vesiclar surface active agent (e.g., a phospholid such as Lipoid E80), and optionally in the presence additives and/or pharmaceutically acceptable excipients such as sucrose and/or sorbitol, and preferably in an aqueous buffer such as a sodium phosphate buffer. Preferably, when the microfluidization is done in two stages or processing steps wherein the first stage is run at a first temperature above the melting point of the drug and the second stage is run at a second temperature below the melting point of the drug, we refer to such a process as a hot melt microfluidization process. A desired amount of a statin can be conveniently added during any step of the process, and is preferably added in the second stage of microfluidization. Water is then subsequently removed from the suspension by a lyophilization (i.e., a freeze-drying step) or spray drying to form a substantially dry powder comprising a solid matrix containing fine particles of fenofibrate and a statin. The water can also be removed by other means such as by evaporation.
In one embodiment of this invention comprising a hot melt process, when the statin is soluble in water or other aqueous media such as aqueous buffer solutions and/or aqueous solutions containing one or more pharmaceutically acceptable excipients or bulking agents such as carbohydrates including sugars, it can be convenient to add the statin to the fenofibrate-containing aqueous medium as either a solid that readily dissolves in the aqueous medium or as an aqueous solution of the statin. A water-soluble statin can be added to the fenofibrate-containing suspensions or dispersions before or after the microfluidization steps, and preferably before or after the second microfluidization step.
In another embodiment of this invention, when the statin is insoluble or poorly soluble in water, it can be micronized in the presence of a surface active substance, preferably a phospholipid, and more preferably with a phospholipid used to stabilize the particles containing fenofibrate, and then mixed with the suspension of fenofibrate before or after any microfluidization steps, and preferably before or after a microfluidization step done below the melting point of fenofibrate.
Optionally, in another embodiment of this invention, the statin and the fenofibrate can be co-suspended and co-micronized in the presence of a phospholipid stabilizing substance to form microparticles comprising the statin and fenofibrate.
In one aspect, small particles of fenofibrate of this invention stabilized by phospholipid can be prepared as a suspension by a process comprising the steps of (a) mixing at high shear an admixture of a fibrate drug and one or more than one surface active substance in an aqueous carrier in the absence of an organic solvent within a first temperature range at or above the melting point of the poorly water-soluble drug to form a heated suspension containing the drug, then (b) homogenizing said heated suspension in a first pressure range and within said first temperature range to form a heated homogenate containing the drug, then (c) cooling said heated homogenate to a second temperature range below the melting temperature of the poorly water-soluble drug to form a transiently stable cooled homogenate containing the drug, then (d) applying a particle stabilizing energetic process to said cooled homogenate within a second temperature range below the melting point of the drug and in a second pressure range to form a cooled dispersion of stabilized small particles of the drug, and then (e) optionally drying the cooled dispersion to form dried matrix of small particles containing the fibrate wherein a statin can be added at any of the previous steps, preferably after the first homogenization step.
In a typical procedure, a premix of fenofibrate, phospholipid Lipoid E80 (dispensed frozen but liquefied or vesiclized at processing temperatures), and optionally sorbitol and sucrose in 10 millimolar aqueous phosphate buffer at pH 8 is microfluidized above the melting temperature of fenofibrate for about 3 to 10 volume passes, cooled, and further microfluidized after addition of a statin for another 10 volume passes to form a suspension of microparticles stabilized by phospholipid.
Particularly important to this aspect of the preparation of the composition of this invention is the use of two homogenization steps separated by a cooling step. The first homogenization step is done on a heated suspension having the poorly water-soluble drug in a molten phase in the presence of one or more than one surface active substance and optionally in the presence of a statin to provide a heated homogenate containing the drug. The heated homogenate is usually in the form of a microemulsion comprising small molten particles or droplets of drug stabilized by one or more than one surface active substance such as a phospholipid substance. The heated homogenate containing the drug is then cooled to provide a transiently stable cooled homogenate containing the drug. The transiently stable cooled homogenate comprises small particles of drug in which the drug is in a solid phase that may be amorphous, crystalline, or a combination of both. The small particles of the cooled homogenate are stabilized by the surface active substance or substances but the particles are transiently stable with respect to particle size growth and eventual precipitation of solid drug from the aqueous carrier unless further processed by an stabilizing energetic step.
The second homogenization step of this aspect of the invention is done on the cooled homogenate after a cooling step to produce a cooled dispersion of small particles containing the drug and having greater stability to particle growth and precipitation than the cooled homogenate. The second homogenization step is a stabilizing energetic process. It provides small particles that are more stable than the transiently stable particles of the cooled homogenate prepared in the first homogenization step and prevents relatively large crystals and/or agglomerates of the poorly water-soluble drug from forming. The second homogenization step facilitates the formation of stabilized small particles of the poorly water-soluble drug. It also provides overall rapid formation of desired small particles containing the poorly water-soluble drug. Optionally, the small particles can be isolated by a drying process, for example by lyophilization or by spray drying. Thus, the process can provide dried small particles containing poorly water-soluble drug. In the absence of the second homogenization step, very large amounts of the poorly water-soluble drug can precipitate from the transiently stable aqueous cooled homogenate or very large amounts of the poorly water-soluble drug can form a sediment by precipitation from the aqueous carrier.
In one aspect of this invention, we have unexpectedly found that small particles containing the poorly water-soluble drug fenofibrate can be prepared by a process comprising the steps of
(a) mixing at high shear an admixture of fenofibrate and a phospholipid substance in an aqueous carrier in the absence of an organic solvent within a first temperature range at or above the melting point of fenofibrate to form a heated suspension wherein fenofibrate is molten;
(b) homogenizing said heated suspension in a first pressure range and within said first temperature range to form a heated homogenate containing fenofibrate;
(c) cooling said heated homogenate to a second temperature range below the melting temperature of fenofibrate to form a transiently stable cooled homogenate containing fenofibrate;
(d) applying a particle stabilizing energetic process to said cooled homogenate within a second temperature range below the melting temperature of fenofibrate and in a second pressure range to form a cooled dispersion of small particles containing fenofibrate, and
(e) doing said cooled dispersion to form dried small particles containing fenofibrate.
In this process, a statin can be added to the admixture, to the heated suspension, to the heated homogenate, to the cooled homogenate, to the cooled dispersion, and optionally to the dried small particles such as in a blending step. At which step in the process the statin can be added to provide the best formulation result in terms of particle size, bioavailability or any other desired property of the formulation can be determined by simple experimentation and process optimization by varying concentrations of the ingredients, temperature, processing time, and the like. Addition of the statin at some time after the cooling of the heated homogenate is currently preferred.
Particularly important to this aspect of the invention is the use of two homogenization steps separated by a cooling step and the use of a phospholipid as a surface active substance. The first homogenization step is done on a heated suspension in the presence of a phospholipid as a surface active substance, in the absence of an organic solvent, and wherein fenofibrate is molten to provide a homogenized microemulsion containing fenofibrate. The second homogenization step is done on a transiently stable cooled homogenate in the presence of the phospholipid and wherein the fenofibrate is a solid to provide a homogenized dispersion of small particles containing fenofibrate. In the absence of the second homogenization step, relatively large crystals of fenofibrate otherwise readily form from the transiently stable cooled homogenate. In the absence of a heated first homogenization step on the molten drug, homogenization of solid fenofibrate to provide a suspension of small particles of fenofibrate takes a prolonged or much longer time in the same homogenization apparatus under substantially the same homogenization conditions of pressure and temperature relative to the time taken in the second homogenization step of this invention, and the properties of the dispersions produced by both routes are not identical.
In a preferred aspect of this invention, a stable combination formulation containing fenofibrate and a statin can be prepared if a desired amount of a statin is added to the cooled homogenate just prior to the energetic process of second homogenization in the above described procedure. The resulting dispersion can be dried such as by freeze-drying or spray drying or other suitable drying method, optionally in the presence of one or more sugars, for example sucrose and/or sorbitol, to provide a matrix of the two drugs in the dried sugar. The fenofibrate comprises dried small particles stabilized by the surface active substance. The sugar can be amorphous or crystalline.
It is an advantage of this invention that small particles containing a poorly water-soluble fibrate drug stabilized with one or more than one surface active substances can be prepared in combination with a statin as a dispersion in an aqueous carrier or as dried small particles.
It is another advantage of this invention that a combination of small particles containing a poorly water-soluble fibrate drug and a statin can be prepared in the absence of an organic solvent.
It is another advantage of this invention that a combination of small particles containing a poorly water-soluble fibrate drug stabilized by a phospholipid surface active substance and a statin can be prepared in the absence of an organic solvent.
It is another advantage of this invention that a dosage form comprising a combination of small particles containing a poorly water-soluble fibrate drug and a statin can be prepared using pharmaceutically acceptable excipients such as phospholipids, sugars and polyols.
It is a further advantage of this invention that a suspension of a combination of small particles containing a poorly water-soluble fibrate drug and a statin can be prepared which suspension is relatively stable to mechanical agitation and to growth of larger crystals of drug over a period of time.
It is another advantage of this invention that a matrix of small particles containing fenofibrate and a statin can be prepared without the use of an organic solvent.
It is a further advantage of this invention that a suspension of small particles containing fenofibrate and a statin can be prepared which suspension is relatively stable to mechanical agitation and to growth of larger crystals of drug over a period of time.
It is a further advantage of this invention that a composition of a combined pharmaceutical dosage form of particles of fenofibrate stabilized by a phospholipid surface active agent and a statin is provided that substantially reduces the difference between the amount of fenofibrate taken up in a patient who is fasting versus the amount of fenofibrate taken up in the same patient who is fed.
It is yet another advantage of this invention that a combination pharmaceutical dosage form of fenofibrate and a statin is provided that can be administered orally such as in a capsule, in a tablet, in a powdered form dispersible in a beverage, or suspended or dissolved in a liquid oil form.
It is still another advantage of this invention that a once-a-day pharmaceutically effective combination dosage form of fenofibrate and a statin is provided that can be administered orally to a patient in need of treatment by the drugs without regard to the amount of food a patient has ingested prior to or following administration of the dosage form.
These and other advantages will be readily apparent from the description of the invention.